March 14, 2014

At the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), Dr. Ron Valdiserri sat down for an in-depth conversation with Dr. Doug Deiterich of the Icahn School of Medicine at Mount Sinai Hospital in New York, who made several presentations and was involved in scientific posters shared during the conference on hepatitis C mono-infection and HIV/HCV co-infection. Dr. Valdiserri and Dr. Dieterich discussed important advances in the diagnosis and treatment of hepatitis C that received a lot of attention at the conference.

Their conversation includes messages for primary care providers and others in the healthcare field, as well as messages for individuals at risk for or living with hepatitis C virus (HCV) infection.

Millions of people throughout the world have diagnosed and undiagnosed chronic liver disease (CLD), including an estimated 40 million in the United States alone, according to the Chronic Liver Foundation. The most common types include chronic hepatitis B and C, alcoholic liver disease, hemochromatosis, nonalcoholic steatophepatits and nonalcoholic fatty liver disease. An aging global population, unhealthy diets and an obesity epidemic have contributed to its increase.

Ultrasound (US) elastography – and to a much lesser extent – magnetic resonance elastography (MRE) are increasingly being used to stage liver fibrosis and follow the impact of treatment by evaluating tissue elasticity in a non-invasive manner. The use of MR and US elastography was the topic of a scientific session at the European Congress of Radiology (ECR) in Vienna, Austria.

Untreated, CLD kills. The prognosis and management of the disease depends on the extent and progression of liver fibrosis. The gold standard for evaluating hepatic fibrosis is percutaneous biopsy followed by a histopathological examination of a liver sample. But this test is invasive, expensive, and because it is highly localized, targets only one small section of the liver.

A bigger picture is provided with US elastography, which was recommended in lieu of biopsy for liver fibrosis diagnosis in January 2013 by the Technology Assessment Centre (NTAC) of the UK's National Health Service. A concurrent economic modelling analysis based upon actual costs published by the York Health Economic Consortium estimated a gross saving of €616 per diagnosis.

Accessible options

The main techniques employed in US elastography are strain, shear wave, transient and acoustic radiation force imaging. Strain US elastography, also described as compression elastography, sonoelastography or real-time elastography, is the most commonly used method, explained Magdalena Wozniak of the Medical University of Lublin, Poland. To perform this exam, radiologists require dedicated software on a conventional higher-class ultrasound scanner, plus a transducer that's compatible with this software.

"The value of US elastography is the relatively low cost of the exam, that it is a proven diagnostic tool and the clinical availability and accessibility of ultrasound scanners," co-author Sabine Bensamoun, from the Université de Technologie de Compiègne in France, told medicalphysicsweb. "Like MRE, the probe sends vibrations inside the liver enabling a radiologist to analyse the displacement of the wave. It provides accurate information on tissue stiffness."

If the exam results merit further investigation, an MRE exam is appropriate. And if a patient is prescribed a hepatic MRI scan, it is easy to add the elastography portion, explained Bensamoun. This entails use of an active driver located outside the magnet room, which generates continuous low-frequency vibrations. The mechanical response to the pressure captures the type of manipulation that a doctor would perform when palpating an abdomen.

MRE is also performed on obese patients in lieu of an initial US elastography exam. The reason, explained Andrzej Pawel Wieczorek, director of the department of paediatric radiology at the Medical University of Lublin and chair of the ECR session, is that US elastography offers only a shallow wave depth. It has difficulty propagating itself with obese patients.

The benefits of MRE are that a comprehensive picture is produced and that all areas of fibrosis can be identified in the liver. "Seeing the total area of the liver through a series of slices enables a radiologist to more easily identify all the locations where the fibrosis is likely to exist. It is so much more comprehensive than biopsy. You can't biopsy 50 locations of suspected fibrosis, but the diagnostic images will show these clearly and also enable a radiologist to assess the surrounding tissue," said Bensamoun. Elastography can display the entire anatomical picture and also the functional properties of the tissue. MRE also is a very accurate way to follow up the patient and the effectiveness of treatment, she explained.

Broader scope

In addition to staging liver fibrosis, elastography is being used to help diagnose and follow treatment of many different types of diseases. Other presentations in the ECR session "Elastography as a new tool" session included the use of US elastography to help diagnose prostate cancer, and MR elastography of the brain to assess cerebral tissue structure. The technology is evolving rapidly, but its value is not as well understood as it should be, according to the presenters.

"Besides liver imaging, quite extensive applications in diagnosis of brain, testicles, breast and lymph nodes have been reported as well, some more extensively than others," Wiczorek told attendees. There are many other directions that are not well established, such as arterial wall/atheromatous plaque characterization, musculoskeletal applications, and diagnostics and evaluation of thrombosis or graft rejection of various transplanted organs.

Elastography is a new tool, and potentially a revolutionary technique that can make a great contribution to diagnostic imaging, the session presenters pointed out. It's time for radiologists to talk about it with their colleagues in medicine.

About the author

Cynthia E Keen is a freelance journalist specializing in medicine and healthcare-related innovations.

Findings Could Influence Process for Allocation of Scarce Organ Resources

PHILADELPHIA — Patients waiting for liver transplants who develop hepatopulmonary syndrome (HPS), a lung disorder associated with end-stage liver disease, are eligible to move up on the wait list. In a new paper published in Gastroenterology, however, Penn Medicine researchers argue the so-called “exception points” given to these patients award some HPS patients unnecessary priority over others on the list, which includes about 17,000 patients

The current U.S. transplant allocation system prioritizes patients based on medical urgency using the Model for End Stage Liver Disease (MELD) score, which takes into account the expected three-month survival due to end-stage liver disease, but does not consider other, unrelated medical complications. As a result, a system that allows wait-list candidates with certain conditions, HPS among them, to be eligible for exception points to increase their waitlist priority has been developed.

HPS is found in approximately 20 percent of patients awaiting liver transplant and is associated with a worse health-related quality of life. The condition is known to double the risk of death among patients evaluated for liver transplantation.

The Penn researchers looked at data from February 2002, the date the exception point program commenced, to December 2012. During this time, 973 patients on the liver transplant list received HPS exception points. While post-transplant survival was similar in HPS vs. non-HPS patients, post-transplant survival in HPS patients varied based on the severity of pre-transplant oxygen saturation levels.

The team found that patients with the poorest oxygen saturation levels (lower than 44 mm Hg) had a significantly lower three-year post-transplant patient survival rate.

Comparatively, significantly more non-HPS waitlisted patients, who did not receive exception points, died on the waitlist or within 90 days of waitlist removal, while a great proportion of HPS waitlist candidates were transplanted (73 percent vs. 43 percent). In addition, the study showed that only 49 percent of HPS transplant recipients had clear evidence of clinical indications for transplantation aside from HPS, as compared with 89 percent of non-HPS transplant recipients.

The findings refute recent reports and demonstrate an association between pre-transplant oxygen levels and post-transplant mortality, suggesting that the criteria for doling out exception points be adjusted based on patients’ oxygenation, and suggesting an over-prioritization of all HPS patients in the current system.

This study represents the largest analysis of liver transplant waitlist candidates with HPS to date.

“These data, we hope, can provide some guidance to UNOS, as the exception point policy comes under revision,” says Goldberg. “As organs are a scarce resource, we want to make it easier for the patients in the most urgent need to be prioritized as such, according to evidence-based criteria.”

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.

Researchers at the Sahlgrenska Academy have identified a gene, which explains why certain patients with chronic hepatitis C do not experience relapse after treatment. The discovery may contribute to more effective treatment.

More than 100 million humans around the world are infected with hepatitis C virus. The infection gives rise to chronic liver inflammation, which may result in reduced liver function, liver cirrhosis and liver cancer. Even though anti-viral medications often efficiently eliminate the virus, the infection recurs in approximately one fifth of the patients.

Prevents incorporation in DNA

Martin Lagging and co-workers at the Sahlgrenska Academy have studied an enzyme called inosine trifosfatas (ITPase), which normally prevents the incorporation of defective building blocks into RNA and DNA.

Unexpectedly they found that the gene encoding for ITPase (ITPA) had significance for the treatment outcome in chronic hepatitis C virus infection.

Five times lower risk

Earlier studies had shown that approximately one third of all people carry variants of the ITPA gene that result in reduced ITPase activity. The research team at the Sahlgrenska Academy showed that patients with these gene variants exhibited a more than a five times lower risk of experiencing relapse after treatment.

Relapse a significant problem

The study encompassed over 300 patients and was carried out in cooperation with hepatitis researchers in several Nordic countries.

- Relapse after completed treatment is a significant problem in chronic hepatitis C, and the results may contribute to explaining why the infection recurs in many patients. Our hypothesis is that a low ITPase activity results in defective nucleotides being incorporated into the virus RNA, which makes the virus unstable, Martin Lagging said.

Important to other virus infections

According to Martin Lagging, the discovery may also have significance for other virus infections.

- A medication that interferes with the enzyme’s activity could have a broad antiviral effect, but this must be further investigated in future studies.

The article Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3 was published online in the journal Hepatology on 13 January 2014.

NEW HAVEN, Conn., March 14, 2014 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced that two oral presentations were made at the 23rd Asian Pacific Association for the Study of the Liver (APASL) Conference 2014 in Brisbane, Australia. Updated Phase 2 clinical trial results evaluating a 150 mg loading dose followed by 50 mg once daily of ACH-3102 in combination with either once daily 200 mg or 400 mg of sovaprevir and twice daily ribavirin showed that 100% of patients achieved SVR12 (n=8) including subjects who had Y93 mutations at baseline. A second oral presentation on ACH-3102 was made at APASL 2014 that discussed clinical virology and the lack of virologic breakthrough that was observed in the novel Phase 2 clinical trial evaluating ACH-3102 with ribavirin for patients with treatment-naïve genotype 1b HCV. Despite the presence of up to six linked mutations identified at baseline in the NS5A protein, ACH-3102, without the co-administration of interferon or a second direct-acting antiviral, was able to suppress viral replication with no virologic breakthrough observed during 12 weeks of treatment.

Reprints of the oral presentation slides and poster will be accessible from the Achillion website at http://www.achillion.com.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's discovery, clinical development, and commercial teams have advanced multiple novel product candidates with proven mechanisms of action into studies and toward the market. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Cautionary Note Regarding Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including the following: the potential benefits of ACH-3102 as an agent to treat HCV-infected patients; and our plans to initiate additional clinical trials of ACH-3102 in combination with other compounds. Achillion may use words such as "expect," "anticipate," "project," "intend," "plan," "aim," "believe," "seek," " estimate," "can," and "may" and similar expressions to identify such forward-looking statements. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: demonstrate in any current and future clinical trials the requisite safety, efficacy and combinability of its drug candidates; advance the preclinical and clinical development of its drug candidates, including ACH-3422, ACH-3102 and ACH-2684, under the timelines it projects in current and future clinical trials; satisfactorily respond to the clinical hold placed on sovaprevir by the FDA; obtain and maintain necessary regulatory approvals; obtain and maintain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; manage litigation; raise the substantial additional capital needed to achieve its business objectives; and successfully execute on its business strategies. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Quarterly Report on Form 10-K for the year ended December 31, 2013, filed on March 7, 2014, and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any duty to update any forward-looking statement, except as required by applicable law.

FAIR USE NOTICE:

This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. It is being made available in an effort to advance the understanding of Hepatitis C, New hepatitis c drugs, Related clinical trials and ongoing research, HIV/HCV coinfection, HIV/AIDS, Other factors of liver disease, and so on. It is believed that this constitutes a 'fair use' of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes. If you wish to use copyrighted material from this site for purposes of your own that go beyond 'fair use', you must obtain permission from the copyright owner.

The material in this site is provided for educational and informational purposes only, and is not intended to be a substitute for a health care provider's consultation. Please consult your own appropriate health care provider about the applicability of any opinions or recommendations with respect to your own symptoms or medical conditions. The information on this site does not constitute medical or health related advice.